Pain is a symptom of many diseases, which makes patients feel pain and may further cause physiological dysfunction. Some long-term severe pain is an unbearable torment to the body. More than one-third of the world's population is suffering from persistent or recurrent pain. The treatment of pain is mainly based on drug therapy. Common analgesics may be classified as follows: non steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, non-opioid central analgesics, spasmolytic analgesics, and the like, wherein opioid analgesics mainly act on opioid receptors. Opioid receptors are mainly divided into three categories: μ receptors, κ receptors, and δ receptors, each of which has different subtypes. An opioid receptor agonist refers to an agonist mainly acting on μ receptors, such as morphine, which exerts an analgesic effect by stimulating the μ receptors and mimicking an endogenous opioid peptide. A partial agonist of an opioid receptor is an agonist for some receptor subtypes and an antagonist for others, also known as a mixed agonist-antagonist of opioid receptor, such as pentazocine, butorphanol, dezocine, etc. An opioid receptor antagonist has competitive antagonism for various opioid receptors, and has antagonistic strengths followed by μ>κ>δ receptors, such as naloxone, which has a chemical structure similar to that of morphine, except that the N-methyl group of morphine is substituted with an allyl group and the 6-hydroxyl group is changed to a keto group, while its pharmacological action is completely opposite to that of morphine.
From a clinical point of view, an ideal analgesic drug should have the following characteristics: 1) a potent analgesic effect; 2) a noninvasive and convenient way of administration, and quick-acting; 3) a long interval between medications; 4) a low peak-to-valley ratio and a stable plasma concentration; 5) a complete metabolism and non-toxic metabolites; and 6) less adverse reactions and mild degree of adverse reactions.
Dezocine, chemical name: 13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylenebenzocyclodecen-3-ol, CAS: 53648-55-8, has the following structural formula:

Dezocine is a potent opioid analgesic, which is an opioid receptor-mixed agonist-antagonist fully agonistic to κ receptors and only having a weaker effect on μ receptors. When the blood concentration of dezocine reaches 5-9 μg/L, it produces a potent analgesic effect, which is 5-9 times that of pethidine and equivalent to that of morphine (Strain E C, Preston K L, Liebson I A. Opioid antagonist effects of dezocine in opioid-dependent humans. Clin Pharmacol Ther, 1996, 60(2): 206-217). Studies have shown that the spinal cord κ receptor is an important target for the analgesic effect of dezocine. Dezocine is absorbed quickly and distributed rapidly and has a long half-life in the body, thus has quick onset of analgesia and long-lasting analgesia, and analgesic intensity, onset time and duration comparable to those of morphine, but is less addictive, and is mainly used in the treatment of patients with moderate to severe postoperative pain and chronic pain, viscera angina and cancer pain and other patients with poor analgesic effect or severe side effects in clinical practice.
It is found that adverse reactions occur when the average peak concentration of dezocine reaches 45 μg/L. Common adverse reactions of dezocine include somnolence, nausea, emesis, etc., and adverse reactions such as dizziness, anorexia, disorientation, hallucinations, sweating, tachycardia, and skin reactions at the injection site have also been reported. In addition, dezocine has slight respiratory and circulatory inhibition, which limits the use of dezocine in patients with reduced respiratory reserve, so it needs to be used in hospitals in order to detect respiratory depression in time and conduct appropriate treatment, which virtually reduces the compliance of patients. In terms of addiction, dezocine may cause dysphoria, sedation and mental dependence damage as well as miosis in a dose-dependent manner (Zhou Panke, Lan Zhixun. Research progress on the application of dezocine in postoperative analgesia. Practical Journal of Clinical Medicine, 2011, 8(6): 169-172). At present, only dezocine in injection form has been listed at home and abroad, which limits its application to some extent.
Polyethylene glycol (PEG) modification is a technology for linking activated PEG to a drug molecule or surface, which a novel drug delivery technique developed rapidly in recent years. Patent application CN201080037610.9 discloses conjugates of oxycodone, morphine and codeine covalently linked to polyethylene glycol. The conjugates were subjected to pharmacokinetic analysis by intravenous injection or oral administration of equal doses in rats. Wherein, compared with oxycodone, intravenous administration of PEGylated oxycodone having different oligomeric PEG-lengths (PEG1-PEG9) resulted in variable plasma concentrations and exposures, wherein PEGylated oxycodone having PEG chain lengths of 3, 5, 7 and 9 showed a higher average exposure, PEGylated oxycodone of PEG6 showed a comparable average exposure, and PEGylated oxycodone having a EPG chain length of 1, 2 or 4 showed a slightly lower average exposure. Oral administration of PEGylated oxycodone having different oligomeric PEG-lengths (PEG1-PEG9) resulted in an increase in plasma exposure, with the exception of oxycodone covalently linked to PEG1 and PEG3. The oxycodone covalently linked to mPEG6 had the highest oral bioavailability, followed by mPEG5-oxycodone and mPEG7-oxycodone. Compared with morphine, administration of PEGylated morphine having different PEG-lengths (PEG1-PEG9) resulted in a higher plasma concentrations and exposure; and oral administration of PEG-morphine conjugates resulted in a decrease in oral bioavailability. Among the morphine conjugates with different PEG lengths, PEG4-morphine conjugate showed the greatest bioavailability. Compared with codeine, PEGylated codeine having different oligomeric PEG-lengths (PEG1-PEG9) has only a slight increase in plasma exposure, and the bioavailability of the orally administered PEG-codeine conjugates increased as the PEG-length increased from 2, and the codeine conjugate with PEG6 had the greatest bioavailability. It can be seen that although the above drugs are all opioid receptor agonists, PEGylated drugs may have different effects for different drugs, and the PEGylated drugs with different PEG lengths may have different effects for the same drug. In the above patent application, each terminal group of polyethylene glycol molecule only binds to one drug molecule, which results in an excessively low drug molecule loading rate, and causes a large pressure on pharmaceutical preparation.